ClinVar Miner

Submissions for variant NM_002485.4(NBN):c.1925A>G (p.Lys642Arg) (rs587781547)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129561 SCV000184343 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000204812 SCV000260089 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 642 of the NBN protein (p.Lys642Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs587781547, ExAC 0.009%). This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 141169). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000204812 SCV000475289 uncertain significance Microcephaly, normal intelligence and immunodeficiency 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000129561 SCV000903603 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780524 SCV000917854 uncertain significance not specified 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The NBN c.1925A>G (p.Lys642Arg) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant . This variant was found in 5/245914 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic NBN variant (0.000125). The variant has not, to our knowledge, been reported in HBOC affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Prostate Cancer Research Center,Institute of Biosciences and Medical Technology, University of Tampere RCV000206550 SCV000259016 uncertain significance Malignant tumor of prostate no assertion criteria provided research

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